The unremitting devastation wrought by the AIDS pandemic will likely only be controlled when a vaccine is developed that is safe, effective, affordable, and simple enough to permit implementation in developing countries where AIDS is most severe. To address this essential goal, the Emory IPCAVD Program will pursue a complementary series of studies of AIDS vaccines that express consensus multi-subtype, multigene HIV-1 antigens in the context of more highly immunogenic variants of modified vaccinia Ankara (MVA). Our efforts to improve upon the favorable practical properties but unsatisfactory immunogenicity of available MVA-based vaccines rest on a series of technical advances and basic insights emerging from our collaborative HIVRAD research efforts. These advances include: development of novel methods to generate unique genetic variants of MVA; the definition of the preferential tropism of MVA for dendritic cells; and elucidation of the consequences of virus infection on these key antigen-presenting cells (APCs). Based on these advances, we developed genetic variants of MVA that more effectively promote APC recruitment, maturation and the effectiveness of antigen presentation, and that yield vaccine vectors with substantially greater immunogenic potential. We now intend to extend these findings to (1) develop even more immunogenic MVA-based AIDS vaccine candidates; (2) to develop vaccine regimens that are simpler, yet more effective than traditional methods of vaccine administration via specific targeting of easily accessible, but immunologically potent APCs; and (3) to better define the developmental processes by which effective memory T cell responses may be elicited by vaccination and how these differ in character from those that follow natural HIV infections. Following an accelerated developmental timeline, we propose to advance our lead MVA-based HIV vaccine candidates into Phase I clinical trials in human volunteers, while we continue to further improve upon the immunogenic properties of and methods of delivery for MVA-based vaccines.